The specific aims of this project are two-fold: 1) Since p-methoxyamphetamine (PMA) has proved to be a useful tool, it is proposed to continue and expand our investigations in comparing the effects of p-methoxyamphetamine and d-amphetamine (A) on brain catecholamines. PMA, unlike A, is a poor central stimulant and does not induce stereotyped behaviors. Biochemical studies indicate that PMA, like A, markedly enhances norepinephrine (NE) release in the cortex but, unlike A, only weakly increases dopamine (DA) release in the neostriatum. Also, PMA was found to be only 14% as effective as A in blocking DA uptake in neostriatum. The poor central stimulatory action of PMA appears to be due to its inability to release and block reuptake of DA in the neostriatum. In support of this conclusion, the use of low doses of DA receptor stimulants such as apomorphine conveys marked central stimulating actions to PMA. Thus, the continued study of PMA-catecholamine interactions (and other PMA analogs as well) should be useful in elucidating the action of A and the structural requirements of the amphetamine-like drugs to alter catecholamine function. 2) Preliminary evidence suggests that the mechanisms by which chronic A intoxication alters catecholamine function involves modification of the constituents of the synaptic plasma membrane (SPM). We have developed an animal model of chronic A intoxication which appears to simulate closely the syndrome observed in the clinic. Using this model, we plan to examine the role of SPM constituents in modifying catecholamine function which leads to the adverse behaviors caused by chronic A treatment. These data should be useful in providing a basis for understanding those factors which regulate membrane assembly and degradation as well as the acute and chronic actions of centrally acting drugs. BIBLIOGRAPHIC REFERENCES: Hitzemann, Barbara A., Hitzemann, Robert J., Brase, David A. and Loh, Horace H.: Influence of pre-natal d-amphetamine administration on development and behavior of rats. Life Sci. 18:605-612. 1976. Tseng, L. F., Menon, M. K. and Loh, H. H.: Comparative actions of the monomethoxyamphetamines on the release and reuptake of biogenic amines in brain tissue. J. Pharmacol. Exp. Ther., in press, 1976.